Structure of cyclin‐dependent kinase 2 (CDK2) in complex with the specific and potent inhibitor CVT‐313.

CVT‐313 is a potent CDK2 inhibitor that was identified by screening a purine‐analogue library and is currently in preclinical studies. Since this molecule has the potential to be developed as a CDK2 inhibitor for cancer therapy, the potency of CVT‐313 to bind and stabilize CDK2 was evaluated, together with its ability to inhibit aberrant cell proliferation. CVT‐313 increased the melting temperature of CDK2 by 7°C in thermal stabilization studies, thus indicating its protein‐stabilizing effect. CVT‐313 inhibited the growth of human lung carcinoma cell line A549 in a dose‐dependent manner, with an IC50 of 1.2 µM, which is in line with the reported biochemical potency of 0.5 µM. To support the further chemical modification of CVT‐313 and to improve its biochemical and cellular potency, a crystal structure was elucidated in order to understand the molecular interaction of CVT‐313 and CDK2. The crystal structure of CDK2 bound to CVT‐313 was determined to a resolution of 1.74 Å and clearly demonstrated that CVT‐313 binds in the ATP‐binding pocket, interacting with Leu83, Asp86 and Asp145 directly, and the binding was further stabilized by a water‐mediated interaction with Asn132. Based on the crystal structure, further modifications of CVT‐313 are proposed to provide additional interactions with CDK2 in the active site, which may significantly increase the biochemical and cellular potency of CVT‐313. [ABSTRACT FROM AUTHOR]